The fruit of 1000 genomes

1000 genomes study is 'guidebook' to how genes vary

A landmark project that has sequenced 1,092 human genomes from individuals around the world will help researchers to
interpret the genetic changes in people with disease.

The first study to break the '1000 genomes barrier' will enable scientists to begin to examine genetic variations at
the scale of the populations of individual countries, as well as guiding them in their search for the rare genetic
variations related to many diseases.

The vast majority of genetic variation is shared with populations around the world but it is thought that a lot of the
contribution to disease may come from rare variants of genes, found in 1 in 100 people or fewer. Researchers need to
find these rare variants to see who has them and work out how they might contribute to a range of conditions from
multiple sclerosis to heart disease and cancer.

The international team behind the 1000 Genomes Project found that rare gene variants tend to be restricted to
particular geographic regions, because they typically arise from more recent mutations since humans spread across the
world. By, for the first time, drilling down to genetic variants occurring at the scale of 1 in 100 people this study
will enable researchers to interpret an individual's genome in the context of the genetic variation found in their own
national population: identifying differences between genomes from 14 countries from Europe (including the UK) the
Americas, East Asia and Africa.

A report of the research is published this week in the journal Nature.

" Using our data you can now look to see if natural selection has been getting rid of such mutations - giving you a
clue as to how harmful these variants might be. "

Dr Richard Durbin

"We are all walking natural experiments; some of our genes are switched off, some are active,
whilst others are overactive," said Professor Gil McVean of Oxford University, the lead author for the study.
"Our research has found that each apparently healthy person carries hundreds of rare variants of
genes that have a significant impact on how genes work, and a handful (from two to five) of rare changes that have been
identified as contributing to disease in other people.

The study has been designed so that, as well as the genome data, researchers have access to living cells (cell lines)
from all 1,092 of the individuals whose genomes have been sequenced. Scientists can now study how differences in the
biology of these cells correlate with genetic differences.

"There are variations that jump out from the data as looking 'a bit bad for you', for example
mutations in regions that regulate genes are likely to be 'bad news' - possibly doing something dramatic to how cells
behave," said Dr Richard Durbin from the Wellcome Trust Sanger Institute, co-chair of the 1000 Genomes Project.
"Using our data you can now look to see if natural selection has been getting rid of such mutations
- giving you a clue as to how harmful these variants might be."

The team's work is already being used to screen cancer genomes for mutations that might identify therapeutic pathways,
to interpret the genomes of children with developmental disorders and to pin-point variation that leads to increased
risk for complex diseases such as heart disease or multiple sclerosis.

Professor Gil McVean of Oxford University said: "Our research shows that you can take localism much
further: for example, even just within the UK, Orkney islanders will have different variations from mainlanders, and
will be different again from those from other nearby islands. In the future we would like to reach the scale of having
a grid of individuals giving us a different genome every couple of square kilometres but there is a long way to go
before we can make this a reality."

Sir Mark Walport, Director of the Wellcome Trust who part-funded the study, said: "It is quite
remarkable that we have gone from completion of the first human genome sequence in 2003 to being able to sequence more
than a 1000 human genomes for a single study in 2012. This study is an important contribution to our understanding of
human genetic variation in health and disease and the DNA sequences are freely available for analysis and use by
researchers."

Funding

This project was supported by many national and charitable organisations, including the Wellcome Trust the UK Medical
Research Council, the US National Institutes of Health and Science Foundations of China.

Participating Centres

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

Website

The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.